Multitubular enzyme reactors were prepared with immobilized phenylalanine degrading enzymes. Such enzyme reactors effectively reduced phenylalanine levels in minutes when tested in vitro and in vivo. There were no adverse physiological effects in the first hours of application. We plan to study stability and immunogenicity of these enzyme reactors upon short term repeated use. Studies will be performed in animals with experimental phenylketonuria produced by simultaneous administration of p-chlorophenylalanine (an inhibitor of phenylalanine hydroxylase) and phenylalanine. These studies will give us information on the length of time and frequency of use necessary when enzyme reactors are applied for the depletion of phenylalanine in patients with phenylketonuria. Simultaneous immobilization of phenylalanine degrading enzymes and fibrinolytic activators on the inner wall of enzyme reactors will be attempted to reduce thrombogenicity of the reactors in the absence of heparin. Results from this project should enable us to produce enzyme reactors suitable for clinical investigation in patients with phenylketonuria.